The invention relates to the use of high-pressure impulse transients to deliver compounds to cells.
Laser light incident on an absorbing material results in deposition of heat in the irradiated region, resulting in thermal expansion or contraction. Thermal expansion, in particular, may result in the launching of impulse transients which propagate through the material at high velocities. Depending on the nature of the irradiating optical field and the host material, impulse transients can be either acoustic waves, i.e., low-pressure waves propagating at sonic speeds, or shock waves, i.e., high-pressure waves propagating at supersonic speeds. The latter may be generated, for example, when the absorption of laser radiation is followed by a rapid phase change (e.g., evaporation or plasma formation) of the irradiated region.
Shock waves typically have fast rise times, resulting in a discontinuity in pressure, density, particle velocity (i.e., the displacement velocity behind the shock front), and internal energy. For instance, in water, the rise time of a shock wave having a pressure of about 100 kbar is on the order of a picosecond; this corresponds to a shock front having a thickness of about 2-5 nm (Harris and Presles, J. Chem. Phys. 77:5157-5164, 1982).
Shock waves generated in tissue may result in cellular damage. In particular, the effects of waves induced using extracorporeal lithotriptors has been extensively studied (see, e.g. Brummer et al., Ultrasound Med. Biol. 15:229-239, (1989). These experiments show that shock wave-induced cavitation generated following optical absorption may be responsible for the cell damage, and that such damage may cause retardation of rapidly proliferating tissue, such as tumors.
The combination of shock waves and drugs has also been used to kill cells. Holmes et al. (J. Urol. 144:159-163, 1990), for example, describe the treatment of prostate tumors in rats using high-pressure, short-duration waves in combination with cisplatinum. In these experiments, although delayed tumor growth was achieved, an increase in animal mortality (relative to cisplatinum alone) was observed when the applied compound was combined with shock wave therapy. For example, Berens et al. (J. Urol. 142:1090-1094, 1989) used spark-induced pressure waves, followed by therapy with several chemotherapeutic agents, to decrease tumor cell proliferation.
In a related application, following interaction with shock or pressure waves, pressure-sensitive drugs may become toxic, resulting in cell killing. Experiments of this sort are described, for example, in Umemura et al., Jap. J. Canc. Res., 81:962-966 (1990).
For many laboratory and therapeutic situations it is desirable to increase the concentration of compounds within a selective group of cells either ex vivo or in vivo. For example, chemotherapy for cancer is made more effective when the cytotoxic agent can be provided to the tumorous tissue in higher concentrations than in surrounding healthy tissues. Similarly, the success of many gene therapy methods is dependent upon the increased delivery of nucleic acids to certain cell types or body regions. Methods for delivering compounds to certain cell types or locations have been attempted using, for example, retroviral vectors, microinjection, calcium phosphate transfer, asialorosomucoid-polycysine conjergation, lipid-mediated delivery, and electroporation. There are many applications for which these systems are ineffective for increasing the concentration of a chosen compound within a given cell type or for which such a method is otherwise inappropriate.